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Bactericidal action of nafcillin, vancomycin, and three cephalosporins against nafcillin-susceptible and nafcillin-resistant coagulase-negative staphylococci.

Coagulase-negative staphylococci (S. epidermidis, 43 strains; S. warneri, 16 strains; S. haemolyticus, five strains; and others, four strains) were tested by the agar dilution method for nafcillin susceptibility: 53 were susceptible with a minimal inhibitory concentration (MIC) of less than or equal to 2 micrograms/ml; four were of indeterminate susceptibility, MIC = 4-16 micrograms/ml; and 11 were resistant, MIC greater than or equal to 32 micrograms/ml. The bactericidal activities from 0 to 24 hr for nafcillin, vancomycin, cephalothin, cefazolin, and cefamandole, each at 16 micrograms/ml in broth, were determined for all the isolates. The data indicate that a nafcillin agar dilution susceptibility test result of resistance does not consistently predict lack of killing activity by the cephalosporins. It is likely that each cephalosporin would have to be tested against individual coagulase-negative staphylococci in order to determine a suitable therapeutic or prophylactic cephalosporin, if a cephalosporin were to be used. Vancomycin was bactericidal for all the nafcillin-resistant coagulase-negative organisms tested.

Cefamandole↗

Chronic osteomyelitis caused by Staphylococcus aureus: controlled clinical trial of nafcillin therapy and nafcillin-rifampin therapy.

A controlled trial of treatment of chronic osteomyelitis caused by Staphylococcus aureus compared nafcillin alone with nafcillin plus rifampin for a six-week period. Treatment was well tolerated, the only adverse effect being mild neutropenia in four of 18 patients; no toxicity was observed from rifampin. Eight of ten patients in the combined treatment group had a favorable clinical response (with follow-up of two to four years) as compared to four of eight in the nafcillin group (P = .2). Despite the failure to show a statistically significant advantage of rifampin plus nafcillin, we conclude that the combination, along with appropriate surgery, should be considered for patients with chronic staphylococcal osteomyelitis.

Administration, Oral↗

The effect of probenecid on nafcillin disposition.

Five normal male volunteers participated in an open crossover study designed to examine the disposition of nafcillin given intravenously with and without probenecid. Each subject received two 500 mg iv doses of sodium nafcillin seven days apart, one dose without probenecid and another dose during oral probenecid administration of 1.0 Gm at bedtime prior to the study day and 1.0 Gm two hours before the nafcillin dose. Blood and urine samples were collected for 10 hours after nafcillin dosing. Assay for nafcillin concentrations was performed via the cup-plate technique with M. luteus. Administration of probenecid significantly increased and prolonged circulating plasma concentrations of nafcillin. Probenecid administration significantly, decreased the per cent of nafcillin recovered in the urine (30% vs. 16.9%). Probenecid pretreatment increased the ana under the plasma drug concentration-time curve (AUC) two-fold and decreased the total body clearance significantly with decreases in both renal and non-renal clearance. K12/k21 and Vc did not significantly change with probenecid. Because probenecid coadministration did not appear to change nafcillin distribution while increasing and prolonging plasma concentrations, probenecid can be recommended to be given concurrently when high nafcillin plasma concentrations are desirable. Changes in plasma concentrations are apparently due to alterations in both renal and non-renal clearances of nafcillin.

Adult↗

Pharmacokinetics and cerebrospinal fluid concentration of nafcillin in pediatric patients undergoing cerebrospinal fluid shunt placement.

Postoperative infection is among the most common complications in patients with cerebrospinal fluid shunt placement. Nafcillin is often used for prophylaxis but not pharmacokinetic data are available perioperatively in pediatric patients. The objectives of this study were to characterize the pharmacokinetics and determine the cerebrospinal concentrations of nafcillin. Ten patients (mean age 8.0 +/- 5.6 years) received three doses of intravenous nafcillin, 50 mg/kg every 6 h; the first dose was administered 1 h prior to surgery. Multiple blood samples were collected during and after surgery and the cerebrospinal fluid sample was obtained at the time of shunt insertion. Urine samples were collected for 24 h after initiation of nafcillin. Nafcillin was analyzed with an HLPC method. The peak serum concentrations ranged from 22 to 107 micrograms/ml; cerebrospinal fluid concentrations ranged from 0.02 to 0.30 (mean 0.16 +/- 0.11) micrograms/ml. The mean total clearance, renal clearance, apparent volume of distribution, and elimination half-life were 0.90 +/- 0.55 l/kg/h, 0.12 +/- 0.04 l/kg/h, 0.70 +/- 0.52 l/kg, and 0.5 +/- 0.1 h, respectively. 16% of total nafcillin dose was excreted in the urine. A 4-fold variability in total clearance and a 10-fold variation in cerebrospinal fluid concentrations of nafcillin was observed in these patients. Further, the concentrations of nafcillin attained in the cerebrospinal do not appear to be adequate, based on its minimum inhibitory concentration of 0.5 micrograms/ml against very susceptible staphylococci. These data, in addition to the fact that an increasing number of staphylococci are becoming resistant to nafcillin, question the usefulness of prophylactic nafcillin in pediatric patients undergoing shunt procedures.

Adolescent↗

Hepatic and renal dysfunction following nafcillin administration.

OBJECTIVE: To review four cases of combined hepatic and renal toxicity that may be associated with the administration of nafcillin in adults. This type of adverse event with the use of nafcillin has not been previously documented in the literature. DATA SOURCES: References from pertinent articles are identified throughout the text. DATA SYNTHESIS: Nafcillin is a widely used penicillinase-resistant penicillin. In four patients receiving nafcillin doses greater than 9 g/24 hours, changes in renal and hepatic function markers were noted within 72 hours of the initiation of nafcillin therapy. Laboratory values returned toward baseline when nafcillin therapy was discontinued. Elevations in blood urea nitrogen, creatinine, total bilirubin, and lactate dehydrogenase have been previously described in the literature for penicillin-like agents other than nafcillin. The exact mechanism for such toxicities as well as patient risk factors have not been clearly established. CONCLUSIONS: Caution should be taken when initiating nafcillin therapy. Evaluation of renal and liver function tests prior to initiating nafcillin therapy and within the first 72 hours appears warranted. If hepatic and/or renal toxicity is observed, discontinuation of nafcillin should be considered.

Aged↗

Adverse drug reactions in home care patients receiving nafcillin or oxacillin.

Documented adverse reactions to anti-infective agents in patients of a home infusion company were studied to determine whether the prevalence of reactions was greater in patients receiving nafcillin or oxacillin than in those receiving other i.v. antiinfectives. Data on adverse drug reactions (ADRs) were obtained by reviewing the discharge summaries of all patients who received anti-infective therapy in 1990-1994 and the company's quarterly and annual ADR reports for that period. The occurrence of ADRs per total courses of therapy was calculated for groups of antiinfectives, as were intensity and causality. For ADRs to nafcillin and oxacillin, patient demographics and treatment information and outcomes were reviewed. A total of 2488 courses of anti-infective therapy were documented, and ADRs occurred in 10.9%. Nafcillin and oxacillin accounted for 105 courses, with an ADR rate of 31.4%; 99 patients received one of these drugs and 24 had ADRs, with rash and phlebitis the most common ADRs. Thirty-nine patients receiving nafcillin or oxacillin had documented infection with methicillin-sensitive Staphylococcus aureus. Seventy-five patients receiving nafcillin or oxacillin did not have an ADR; therapy was successful in 62 of these patients. Of the 24 patients with ADRs to nafcillin or oxacillin, 13 were switched to other i.v. anti-infectives, which were successful in 10 of them. Five patients were hospitalized because of ADRs to nafcillin or oxacillin. Most nafcillin or oxacillin ADRs that resulted in a therapy change or hospitalization occurred in the second or third week of therapy. Home care patients who received nafcillin or oxacillin therapy had a disproportionately high number of ADRs, compared with patients who received other anti-infective agents.

Adolescent↗

Growth of Staphylococcus aureus with nafcillin in vitro induces alpha-toxin production and increases the lethal activity of sterile broth filtrates in a murine model.

The morbidity and mortality of Staphylococcus aureus infections remain high despite antibiotic therapy. To investigate further the observation that penicillins increase the hemolytic activity of staphylococcal cultures, 37 strains were grown in broth with and without subinhibitory nafcillin. Nafcillin stimulated hemolytic activity in nafcillin-susceptible and -resistant isolates. Sterile broth filtrates of nafcillin-associated cultures injected intraperitoneally in mice were more rapidly lethal than filtrates of the same strain grown without nafcillin. Lethality was neutralized by anti-alpha-toxin antisera. DNA-RNA hybridization revealed a nafcillin-associated increase in alpha-toxin mRNA during the postexponential growth phase after the activation of agr. Isolates grown in slightly inhibitory nafcillin concentrations had more alpha-toxin mRNA than did nafcillin-free cultures, whereas agr RNAIII levels were comparable. This suggests that nafcillin-induced alpha-toxin production is not entirely attributable to agr. A supplemental regulatory mechanism may be involved.

Animals↗

Nafcillin-induced neutropenia in two children.

Two cases of nafcillin-induced neutropenia in children are discussed. A seven-year-old girl was referred to the hospital after the pain and swelling in her foot persisted despite five days of oral penicillin VK therapy. Administration of intravenous nafcillin 150 mg/kg/day was started upon admission. The patient's leukocyte count was normal upon admission; further, her leukocyte and neutrophil counts were normal on the 10th and 17th days of hospitalization. After 22 days of nafcillin therapy, her leukocyte and neutrophil counts fell to 2300 and 162/cu mm, respectively. Three days after the nafcillin was discontinued, the leukocyte count was 5800/cu mm. The patient was given dicloxacillin 50 mg/kg/day, and had no recurrence of neutropenia. The second case involved a 28-month-old girl admitted to the hospital with fever, irritability, and skin rash. Her leukocyte count was normal upon admission. She received 10 days of penicillin G 100,000 units/kg/day, followed by 10 days of nafcillin 150 mg/kg/day, before neutropenia was discovered. On the ninth day of nafcillin therapy, here leukocyte and neutrophil counts were 4200 and 822/cu mm, respectively. Nafcillin was discontinued and cefazolin therapy was initiated at 100 mg/kg/day. Blood counts returned to normal, and there was no recurrence of neutropenia. Differential blood cell counts should be performed on patients receiving nafcillin, and, if neutropenia develops, nafcillin should be discontinued and treatment with a nonpenicillin antimicrobial considered.

Adolescent↗

A rapid analysis of nafcillin using high-performance liquid chromatography.

A simple, rapid, and reproducible high-performance liquid chromatography method is described for the measurement of nafcillin using an internal standard (IS), 5-(p-hydroxyphenyl)-5-phenylhydantoin. A one-step protein precipitation was used for preparation of nafcillin and IS. The mobile phase included 0.02 M ammonium acetate buffered solution and acetonitrile (75:25 vol/vol). An Ultrasphere ODS reversed-phase column was used and the detector was set at 224 nm. The retention time of IS and nafcillin was 4.8 and 6.6 min, respectively. The absolute recovery for nafcillin ranged from 95-98%. The intraday coefficient of variation for the assay was 3.5% at nafcillin concentrations of 1.0 and 60 micrograms/ml. The interday coefficient of variation was 7.1 and 3.1% at the nafcillin concentrations of 1.0 and 60.0 micrograms/ml, respectively. The major advantages of this method include the single-step extraction and the use of a small volume (50 microliter) of serum samples for nafcillin measurement. The serum concentrations of nafcillin in a pediatric patient were determined to demonstrate the application of this method.

Chromatography, High Pressure Liquid↗

Extracellular proteases increase tolerance of Bacillus subtilis to nafcillin.

Mutants of Bacillus subtilis capable of secreting high amounts of protease were highly tolerant to the lethal and lytic effects of nafcillin. Protease-deficient mutants were more susceptible. However, when subtilisin was added to exogenously to a protease-deficient strain, the organism assumed the characteristics of nafcillin tolerance. Similarly, when phenylmethylsulfonyl fluoride, a serine protease inhibitor, was added to the tolerant strains, they became susceptible to nafcillin-induced lysis. The effects of nafcillin on B. subtilis were studied with both viability determinations and assay of cellular lysis. The minimum inhibitory concentrations of nafcillin tended to be higher for the protease hyperproducing strains, but these values could be reduced by the protease inhibitor. No loss of antibiotic activity was observed when nafcillin was incubated with either subtilisin or trypsin. Furthermore, protease and autolysin from B. subtilis were not modified by nafcillin. The results showed that extracellular proteases could render B. subtilis relatively tolerant to the killing and lytic effects of a cell wall antibiotic. The proteases were probably acting on the autolysins of the organism, thereby increasing tolerance to nafcillin.

Bacillus subtilis↗

Disposition of nafcillin in patients with cirrhosis and extrahepatic biliary obstruction.

Nafcillin, a semisynthetic penicillin effective against penicillinase-producing staphylococci, is eliminated largely in man via the liver. This study assessed the effect of cirrhosis and extrahepatic biliary obstruction in man on the pharmacokinetics of nafcillin. The plasma clearance of nafcillin controls was 583 +/- 144.2 ml per min (mean +/- SD) and fell strikingly to 291 +/- 147.6 and 163 +/- 56.3 ml per min in patients with cirrhosis and extrahepatic obstruction, respectively (P less than 0.001). In the latter two groups nafcillin excreted in urine increased from about 30 to 50% of administered dose (P less than 0.02), suggesting that renal disease superimposed on hepatic disease would further decrease over-all nafcillin clearance. The depression of nafcillin clearance with hepatobiliary disease did not correlate with any conventional liver laboratory test. The initial volume of distribution of nafcillin (V1) was unaltered but at steady state (Vd()) there was a significant reduction in the distribution volume in the patients with liver disease. Accordingly, the impairment in drug elimination, as assessed by its clearance from plasma, was underestimated by the prolongation of the nafcillin elimination half-life (t1/2(beta)) which was 1.02 +/- 0.20 hr in controls, and 1.23 +/- 0.31 (P greater than 0.05) and 1.73 +/- 0.44 hr (P less than 0.03), respectively, in patients with cirrhosis and extrahepatic obstruction.

Adult↗

Clinical and pharmacokinetic evaluation of nafcillin in infants and children.

Nafcillin (150 mg/kg/day, divided every six hours) was administered intravenously to 46 patients ranging from 5 to 163 months of age with suspected or proved bacterial infections. Thirteen of 15 patients with bacteriologically proved infection responded to nafcillin. Two patients with cellulitis due to Escherichia coli or to Hemophilus influenzae type b did not improve with nafcillin therapy. A mean serum nafcillin concentration of 48 microgram/ml was observed 30 minutes after a dose of 37.5 mg/kg. The mean serum half-life was 0.76 hours. There was no significant relation between age and serum half-life, volume of distribution, or plasma clearance rate. Two patients developed neutropenia and six other patients developed an eosinophilia greater than 400/mm3 while receiving nafcillin. No significant toxic effect of nafcillin on liver or renal function was observed. One patient had phlebitis. There was a significant correlation between nfacillin concentrations and serum inhibitory and bactericidal titers (P less than 0.001). Results from this study indicate that nafcillin is a safe and effective antibiotic for the treatment of infections due to susceptible bacteria in the dosage tested.

Adolescent↗

Hemodynamic changes after nafcillin administration during coronary artery bypass surgery.

The hemodynamic response to nafcillin administration was studied in 45 patients with good left ventricular function and no known history of hypersensitivity to penicillin during coronary artery bypass grafting (CABG). Group I (15 patients) received 1 gram of nafcillin in 10 mL of saline as an intravenous (IV) bolus, group II (15 patients) received 1 gram of nafcillin in 50 mL of saline as a slow IV infusion over 15 minutes, and group III (15 patients) did not receive nafcillin. Hemodynamic variables and plasma histamine and catecholamine levels were measured before and after nafcillin administration, after 500 mg of CaCl2, and after 0.1 mg of phenylephrine. Bolus nafcillin administration produced profound hypotension secondary to vasodilatation with significant increases in cardiac index and decreases in systemic and pulmonary vascular resistances. Cardiac index increased from 3.15 +/- 0.3 L/min/m2 to 5.75 +/- 0.25 L/min/m2 (P less than 0.005) one minute after nafcillin administration, and remained at 5.1 +/- 0.35 L/min/m2 after administration of CaCl2 (P less than 0.005). All hemodynamic parameters returned toward control values after administration of 0.1 mg of phenylephrine, IV. Plasma epinephrine, norepinephrine, and histamine levels increased more than 100%. In group II, cardiac index increased, while systemic and pulmonary vascular resistances and mean arterial pressure decreased. However, these changes were less significant than those found in group I.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗

Pharmacokinetics of nafcillin in patients with renal failure.

Nafcillin, a pencillinase-resistant penicillin, is frequently used for treatment of staphylococcal infections in hemodialysis patients. Despite its widespread use, there is a paucity of available data regarding the pharmacokinetics of nafcillin in hemodialysis patients. Therefore, sodium nafcillin, 25 mg/kg, was given intravenously over a 5- to 15-min period to 12 hemodialysis patients. Eleven patients were studied during dialysis, and eight of these were studied again during the interdialysis period. The initial serum half-life for nafcillin was 0.208 h during dialyses and 0.278 h between dialyses. The terminal half-life was 1.48 h during dialyses and 1.89 h between dialyses. There was no statistically significant difference between these values. These data indicate that renal failure does not appreciably affect the serum half-life of nafcillin, and hemodialysis does not accelerate the rate of clearance of nafcillin from the blood. Therefore, no modification of the usual nafcillin dosage is necessary when using this drug in hemodialysis patients.

Half-Life↗

The physical state of nafcillin sodium in frozen aqueous solutions and freeze-dried powders.

The purpose of this study was to develop a better understanding of the physical chemistry of freeze drying of lyotropic liquid crystals using nafcillin sodium as a model solute. Solutions and freeze-dried powders of nafcillin sodium were studied by polarized light microscopy, differential scanning calorimetry, x-ray powder diffraction, and water vapor adsorption. Differential scanning calorimetry thermograms of nafcillin sodium solutions contain a melting endotherm at approximately -5.5 degrees C and, depending on the concentration and heating rate, a crystallization exotherm immediately after this endotherm followed by the melting endotherm of ice. When the sample is annealed at -4 degrees C, both the endotherm and exotherm are eliminated, and a new endotherm appears at approximately -1 degree C on the shoulder of the ice-melting endotherm. The data are interpreted as melting of a liquid crystalline phase, followed by crystallization. X-ray powder diffractograms of unannealed freeze-dried nafcillin sodium are consistent with a lamellar liquid crystal. Diffractograms of annealed freeze-dried nafcillin sodium indicate crystalline material which is a different crystal form than the monohydrate starting material. Moisture adsorption isotherms of the freeze-dried annealed (crystalline) and unannealed (liquid crystalline) nafcillin sodium show different affinities for moisture compared to the crystalline starting material. Solid-state stability data demonstrate that the freeze-dried liquid crystalline form of nafcillin sodium is much less stable than the freeze-dried crystal-line material. The literature recognizes two types of solute behavior on freezing, where the solute either crystallizes from the freeze concentrate or remains amorphous. Lyotropic liquid crystal formation during freezing represents a separate category of freezing behavior, the physical chemistry of which is worthy of further investigation.

Calorimetry, Differential Scanning↗

Co-trimoxazole versus nafcillin in the therapy of experimental meningitis due to Staphylococcus aureus.

Co-trimoxazole was compared with nafcillin against Staphylococcus aureus in vitro and in the therapy of experimental Staph. aureus meningitis in rabbits. Co-trimoxazole (trimethoprim:sulphamethoxazole in a 1:20 ratio) was synergistic against 22/24 strains of Staph. aureus in vitro. The MBC90 of co-trimoxazole and nafcillin were 0.156-3.12 mg/l and 0.25 mg/l, respectively, concentrations below those achievable in purulent cerebrospinal fluid. The rate of bacterial killing (Staph. aureus) by co-trimoxazole and nafcillin were similar in both broth and pooled CSF in vitro. However, the MBC increased and the rate of bactericidal activity of both agents declined when tested in CSF at a higher inoculum (10(7) cfu/ml). During continuous intravenous infusion therapy of a reproducible, uniformly fatal (if untreated) model of experimental Staph. aureus meningitis, serum concentrations of all agents closely approximated those found in humans receiving standard parenteral regimens. The mean percent penetration into CSF ([CSF]/[serum] X 100) was 2.9, 35.6 and 27.1% for nafcillin, trimethoprim and sulphamethoxazole, respectively. Although both nafcillin and co-trimoxazole therapy reduced CSF Staph. aureus concentrations significantly more rapidly (P less than 0.001) when compared to untreated controls, the bactericidal rate was modest. The CSF was rendered sterile in 0/64 animals treated with either regimen for 8 h. Nafcillin was more rapidly bactericidal in vivo (P less than 0.03) than co-trimoxazole in this model. Caution is advised in the use of co-trimoxazole for infections of the central nervous system caused by Staph. aureus.

Animals↗

Potentiation of cyclosporine nephrotoxicity by nafcillin in lung transplant recipients.

The interaction between nafcillin and cyclosporine was examined in lung transplant recipients receiving cyclosporine-based immunosuppression. Nine recipients received nafcillin for one week posttransplant and 10 recipients did not receive nafcillin. Age, sex, pretransplant renal function, type of transplant procedure, use of cardiopulmonary bypass, and initial cyclosporine dose were not significantly different between groups. The degree of renal dysfunction during the early postoperative period was significantly greater in the lung recipients receiving nafcillin. Although cyclosporine doses were significantly higher in the nafcillin group, this was not reflected by differences in cyclosporine levels. No difference in survival or incidence of allograft rejection was seen--however, the incidence of viral infection was significantly higher in the patients who received nafcillin. Based on our findings the use of an alternative antibiotic for antistaphylococcal prophylaxis in transplant recipients receiving cyclosporine is recommended.

Adolescent↗

Nafcillin concentration in cerebrospinal fluid during treatment of staphylococcal infections.

The nafcillin concentration of simultaneous cerebrospinal fluid (CSF) and serum specimens from nine patients being treated with parenteral nafcillin for staphylococcal infection were measured. Marked variations in the ratio of CSF/serum nafcillin concentration were observed. However, the concentration of nafcillin in the CSF was greater than the minimum lethal concentration (MLC) for Staphylococcus aureus in eight of the nine patients. In five patients with CSF pleocytosis, the nafcillin concentration was three to 100 times the MLC. These results support the recommendation to use nafcillin in doses of at least 100 to 200 mg/kg body weight-day for treatment of meningitis caused by S. aureus.

Adolescent↗